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Sponsored by: |
National Institute of Neurological Disorders and Stroke (NINDS) |
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Information provided by: | National Institutes of Health Clinical Center (CC) |
ClinicalTrials.gov Identifier: | NCT00547911 |
An experimental drug called L-DOPS increases production in the body of a messenger chemical called norepinephrine. Cells in the brain that make norepinephrine are often gone in Parkinson disease. The exact consequences of this loss are unknown, but they may be related to symptoms such as fatigue, depression, or decreased attention that occur commonly in Parkinson disease. This study will explore effects of L-DOPS in conjunction with carbidopa and entacapone, which are drugs used to treat Parkinson disease. We wish to find out what the effects are of increasing norepinephrine production in the brain and whether carbidopa and entacapone augment those effects.
Volunteers for this study must be at least 18 years of age and able to give consent to participate in the study. To participate in the study, volunteers must discontinue use of alcohol, tobacco, and certain herbal medicines or dietary supplements, and must also taper or discontinue certain kinds of medications that might interfere with the results of the study. Candidates will be screened with a medical history and physical exam.
Participants will be admitted to the National Institutes of Health Clinical Center for two weeks of testing. The study will have three testing phases in a randomly chosen order for each participant:
Each phase will last two days, with a washout day between each phase in which no drugs will be given and no testing will be performed. In each phase, participants will undergo a series of tests and measurements, including blood pressure and electrocardiogram tests. Participants who are healthy volunteers will also have blood drawn and will undergo a lumbar puncture (also known as a spinal tap) to obtain spinal fluid for chemical tests.
Condition | Intervention | Phase |
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Parkinson Disease Multiple System Atrophy Autonomic Nervous System Diseases |
Drug: L-DOPS |
Phase I Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Active Control, Crossover Assignment, Pharmacokinetics/Dynamics Study |
Official Title: | L-Dihydroxyphenylserine (L-DOPS) for Norepinephrine Deficiency: Interactions With Carbidopa and Entacapone |
Estimated Enrollment: | 70 |
Study Start Date: | October 2007 |
L-DOPS is a synthetic chemical that can be converted to norepinephrine (NE). NE is a key messenger of the sympathetic nervous system. Failure of the sympathetic nervous system results in orthostatic hypotension (OH), a fall in blood pressure when the person stands up. Patients with Parkinson disease (PD) often have OH that is related to loss of sympathetic nerves and to NE deficiency. L-DOPS can help treat OH in these patients. Drugs used commonly to treat PD, however, probably influence effects of L-DOPS. Carbidopa, which combined with levodopa (brand name Sinemet) is a standard treatment for PD, might prevent L-DOPS from being turned into NE outside the brain and therefore interfere with effects of L-DOPS on blood pressure. Entacapone (brand name Comtan) might augment production of NE after a dose of L-DOPS, by decreasing metabolic breakdown of L-DOPS. The first goal of this study is to test these hypotheses in patients with neurogenic OH. NE is also a chemical messenger in the brain and is thought to participate in a variety of neuropsychiatric phenomena such as vigilance, mood, memory, and transmission of pain sensation. Patients with OH can have evidence of central NE deficiency. A second goal of this study is to determine whether depressed mood, apathy, fatigue, or pain improve with L-DOPS treatment in these patients.
A third goal is to test whether carbidopa and entacapone, which both should enhance delivery of L-DOPS to the brain, augment L-DOPS effects on these symptoms. Finally, a fourth goal is to verify that carbidopa and entacapone augment neurochemical indices of central neural production of NE after a dose of L-DOPS.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | Yes |
All subjects in this Protocol will have already undergone clinical laboratory evaluations called for in Clinical Protocol 03-N-0004, "Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure.
EXCLUSION CRITERIA:
Age: People younger than 18 years old are excluded.
Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator or Clinical Director, Protocol participation would place the subject at substantially increased acute medical risk. This includes the risks associated with air travel to the NIH. A candidate subject is excluded if, in the opinion of the Principal Investigator or Clinical Director, the medical risk outweighs the potential scientific benefit.
Disqualifying Conditions: A candidate subject is excluded if there is a disqualifying condition. Examples of disqualifying conditions are hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, and symptomatic coronary heart disease. Persons with dementia interfering with their ability to provide informed consent are excluded. If dementia is suspected, such as by score on the mini-mental examination of less than 24, then a bioethics consult will be obtained.
Medications: A candidate subject is excluded if clinical considerations require that the patient continue treatment with a drug likely to interfere with the scientific results. Examples would be treatment with levodopa/carbidopa or a tricyclic antidepressant. Patients with known or suspected allergy or hypersensitivity to any test drug are excluded. Patients unable to discontinue nicotine or alcohol temporarily are excluded. Patients are not to discontinue any medications before the patient or the patient's doctor discusses this with Dr. Goldstein, the Principal Investigator, or Sandra Pechnik, the Research Nurse. If it is decided that discontinuing medications would be unsafe, then the patient is excluded from the study. Subjects must discontinue use of alcohol and tobacco throughout the period of testing. PD patients who have difficulty tolerating withdrawal of levodopa/carbidopa treatment may be treated with a dopamine receptor agonist during the study, with the dosing remaining the same.
Tricyclic antidepressants, drugs that inhibit L-aromatic-amino-acid decarboxylase or catechol-O-methyltransferase, levodopa, and carbidopa will be withdrawn throughout the period of study. Withdrawal of antiparkinsonian medications may worsen rigidity, bradykinesia, or tremor. These effects are not thought to adversely influence the long-term course of the disease. Withdrawal of tricyclic antidepressants may worsen depression. Drug withdrawal will be done only in inpatients. Alternative drugs, such as serotonin reuptake blockers, anti-anxiety agents, or dopamine receptor agonists, may be used at constant doses during the study.
Herbal Medicines and Dietary Supplements: Certain herbal medicines or dietary supplements are known or suspected to interfere with the experimental results, and such herbal medicines or dietary supplements must be discontinued before enrollment in the study. For many herbal medicines or dietary supplements, the mechanisms of action and therefore the possible effects on the experimental results are unknown. In cases where the subjects wish to continue their herbal medicines or dietary supplements while on study, and search of the available medical literature fails to identify effects that are known or expected to interfere with the experimental results, then the subjects may participate.
Practical Limitations: Subjects in whom we feel it would be difficult to insert a catheter into a vein are excluded. Subjects who are not expected clinically to tolerate lying still supine during the testing are excluded.
Pregnancy: Pregnant or lactating women are excluded. Women of childbearing potential must have a negative urine or blood test for pregnancy done within 24 hours before any testing involving radioactivity or an experimental drug.
Post-Lumbar Puncture Headache: Candidate Healthy Volunteers are excluded if they had a headache requiring a blood patch after lumbar puncture under fluoroscopic guidance.
Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
Contact: TTY | 1-866-411-1010 |
United States, Maryland | |
National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
Bethesda, Maryland, United States, 20892 |
Responsible Party: | National Institutes of Health ( David S. Goldstein, M.D./National Institute of Neurological Disorders and Stroke ) |
Study ID Numbers: | 080012, 08-N-0012 |
Study First Received: | October 19, 2007 |
Last Updated: | May 7, 2009 |
ClinicalTrials.gov Identifier: | NCT00547911 History of Changes |
Health Authority: | United States: Federal Government |
Entacapone Carbidopa Locus Ceruleus/Norepinephrine-Autonomic System Norepinephrine Adrenergic Nervous System |
Pathological Conditions, Anatomical Neurotransmitter Agents Adrenergic alpha-Agonists Ganglion Cysts Adrenergic Agents Carbidopa Basal Ganglia Diseases Central Nervous System Diseases Cardiovascular Agents Brain Diseases Neurodegenerative Diseases Adrenergic Agonists |
Entacapone Dopamine Autonomic Nervous System Diseases Multiple System Atrophy Parkinson Disease Movement Disorders Norepinephrine Vasoconstrictor Agents Dopamine Agents Atrophy Peripheral Nervous System Agents Parkinsonian Disorders |
Pathological Conditions, Anatomical Neurotransmitter Agents Adrenergic Agents Molecular Mechanisms of Pharmacological Action Anti-Dyskinesia Agents Basal Ganglia Diseases Physiological Effects of Drugs Antiparkinson Agents Neurodegenerative Diseases Brain Diseases Adrenergic Agonists Autonomic Nervous System Diseases Movement Disorders Therapeutic Uses Vasoconstrictor Agents |
Adrenergic alpha-Agonists Sympathomimetics Carbidopa Nervous System Diseases Central Nervous System Diseases Enzyme Inhibitors Cardiovascular Agents Pharmacologic Actions Entacapone Multiple System Atrophy Autonomic Agents Parkinson Disease Norepinephrine Atrophy Dopamine Agents |